Structural Activation of Pro-inflammatory Human Cytokine IL-23 by Cognate IL-23 Receptor Enables Recruitment of the Shared Receptor IL-12Rβ1

Yehudi Bloch, Laura Bouchareychas, Romain Merceron, Katarzyna Składanowska, Lien Van den Bossche, Sammy Detry, Srinath Govindarajan, Dirk Elewaut, Filomeen Haerynck, Melissa Dullaers, Iannis Adamopoulos, Savvas N. Savvides

Research output: Contribution to journalArticlepeer-review

62 Scopus citations


Interleukin-23 (IL-23), an IL-12 family cytokine, plays pivotal roles in pro-inflammatory T helper 17 cell responses linked to autoimmune and inflammatory diseases. Despite intense therapeutic targeting, structural and mechanistic insights into receptor complexes mediated by IL-23, and by IL-12 family members in general, have remained elusive. We determined a crystal structure of human IL-23 in complex with its cognate receptor, IL-23R, and revealed that IL-23R bound to IL-23 exclusively via its N-terminal immunoglobulin domain. The structural and functional hotspot of this interaction partially restructured the helical IL-23p19 subunit of IL-23 and restrained its IL-12p40 subunit to cooperatively bind the shared receptor IL-12Rβ1 with high affinity. Together with structural insights from the interaction of IL-23 with the inhibitory antibody briakinumab and by leveraging additional IL-23:antibody complexes, we propose a mechanistic paradigm for IL-23 and IL-12 whereby cognate receptor binding to the helical cytokine subunits primes recruitment of the shared receptors via the IL-12p40 subunit. IL-23, a human cytokine under intense clinical targeting, is pivotal to cellular responses underlying widespread inflammatory and autoimmune diseases, such as psoriasis and rheumatoid arthritis. Bloch et al. determine the structure of IL-23 bound by one of its receptors, IL-23R, and reveal how IL-23R activates IL-23 for recruiting IL-12Rβ1 to the signaling assembly. Together with identifying an interaction hotspot, such findings may contribute to additional approaches for the mechanistic and therapeutic interrogation of receptor complexes mediated by IL-12 family members.

Original languageEnglish (US)
Pages (from-to)45-58.e6
Issue number1
StatePublished - Jan 16 2018


  • Crohn's disease
  • cytokine-receptor complex
  • IL-12Rβ1
  • IL-23
  • IL-23 receptor
  • inflammation
  • inflammatory bowel disease
  • psoriasis
  • rheumatoid arthritis
  • structure

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases


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